GSK衛(wèi)星會_替諾福韋的臨床應用_課件

1、替諾福韋的臨床應用黃元成 教授 華中科技大學同濟醫(yī)學院附屬同濟醫(yī)院縮略詞表NAs 核苷（酸）類似物ADV阿德福韋酯LAM拉米夫定ETV恩替卡韋LdT替比夫定TDF富馬酸替諾福韋二吡呋酯FTC恩曲他濱BMD骨密度HCC肝細胞肝癌目錄慢乙肝抗病毒治療的目標與現(xiàn)狀替諾福韋在NAs初治慢乙肝患者中的療效和耐受性替諾福韋在NAs經(jīng)治慢乙肝患者中的療效和耐受性123 慢乙肝治療目標是持久抑制病毒復制和阻止疾病進展治療首要目標是持久抑制HBV復制。短期治療目標是達到“初步應答”，即HBeAg血清學轉(zhuǎn)換和（或）HBV DNA抑制，ALT水平恢復正常，預防肝臟失代償，達到“持久應答”，降低肝臟炎癥壞死和肝纖維化

2、的發(fā)生.最終治療目標是預防肝臟失代償、減少或預防進展為肝硬化和（或）HCC，并延長生存期。1提高CHB患者的生活質(zhì)量和延長生存期，防止疾病進展為肝硬化、失代償期肝硬化、終末期肝病、肝癌和死亡，達到該目標需要持續(xù)抑制HBV復制2治療CHB目標是持續(xù)抑制HBV復制和延緩疾病進展。最終目標是預防肝硬化、肝衰竭和肝癌3最大限度地長期抑制HBV, 減輕肝細胞炎癥壞死及肝纖維化, 延緩和減少肝臟失代償、肝硬化、HCC 及其并發(fā)癥的發(fā)生, 從而改善生活質(zhì)量和延長存活時間441 Liaw YF, Kao JH, Piratvisuth T, et al. Asian-Pacific consensus sta

3、tement on the management of chronic hepatitis B: a 2012 update. Hepatol Int. 2012;6(3):531-561 ；2 European Association For The Study Of The Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol. 2012;57(1):167-85；3 Anna S. F. Lok, Brian J. McMahon. Ch

4、ronic Hepatitis B: Update 2009.Hepatology. 2009;50(3):1-36；4 中華醫(yī)學會肝病學分會，中華醫(yī)學會感染病學分會。慢性乙型肝炎防治指南（2010版）。中華肝臟病雜志。2011;19(1):13-242012 歐肝指南2009 美肝指南2012 亞太共識2010 中國指南中國慢乙肝抗病毒藥物發(fā)展史在過去的幾十年中，慢乙肝抗病毒治療取得了巨大的進步目前，在中國上市的慢乙肝抗病毒藥物共有兩大類，包括干擾素和NAsSun J, Hou JL, et al. Management of chronic hepatitis B: experience

5、from China. Journal of Viral Hepatitis, 2010,17(suppl. 1):10-17.普通干擾素 1992LAM 1999聚乙二醇干擾素-2aADV2005ETV 2006聚乙二醇干擾素-2bLdT2007TDF2013(國際2008)替諾福韋具有高抗病毒效力所引用數(shù)據(jù)來自非頭對頭研究*替諾福韋采用HBV DNA400拷貝/ml,其他采用HBV DNA300拷貝/mlLau DT, Bleibel W.Current status of antiviral therapy for hepatitis B. Therap Adv Gastroentero

6、l. 2008;1(1):61-75不同口服抗病毒藥物治療48或52周的病毒學應答迄今為止，尚未檢測到替諾福韋相關耐藥 第6年2 第7年3 第8年4 0 0 0 替諾福韋和其他核苷（酸）類似物長期治療初治慢性乙肝患者的耐藥率11 European Association For The Study Of The Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol. 2012;57(1):167-85；2 Kitrinos KM, Corsa

7、A, Liu Y, et al. No detectable resistance to tenofovir disoproxil fumarate after 6 years of therapy in patients with chronic hepatitis B. Hepatology. 2014;59(2):434-42; 3 Buti M, Tsai N, Petersen J, et al. Seven-year efficacy and safety of treatment with tenofovir disoproxil fumarate for chronic hep

8、atitis B virus infection. Dig Dis Sci. 2015 May;60(5):1457-64.4 Marcellin P et al. Long Term Treatment with Tenofovir Disoproxil Fumarate for Chronic Hepatitis B Infection is Safe and Well Tolerated and Associated with Durable Virologic Response with no Detectable Resistance: 8 Year Results from Two

9、 Phase 3 Trials. Hepatology, Volume 60, Number 4 (suppl) AASLD Abstracts 229.目錄慢乙肝抗病毒治療的目標與現(xiàn)狀替諾福韋在NAs初治慢乙肝患者中的療效和耐受性替諾福韋在NAs經(jīng)治慢乙肝患者中的療效和耐受性123TDF 300 mg(n=250, 176)ADV 10 mg(n=125, 90)開放標簽 TDF 300 mg 每日一次肝活檢時間8543012研究時限（年）1 Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate ver

10、sus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008;359:24422455; 2 Marcellin P, Gane E, Buti M, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet. 2013;381(9865):468-75; FTC/TDF在中國并未

11、被批準用于治療慢乙肝患者 641例CHB患者2:1隨機分組 替諾福韋治療初治慢乙肝患者：研究設計（102/103研究）主要研究終點：48周血清HBV DNA400拷貝/ml和組織學改善的患者比例。組織學改善：Knodell壞死性炎癥評分下降2分且肝纖維化未加重。72周或以后，HBV DNA400 拷貝/ml的患者可加用恩曲他濱（FTC），共57例患者符合加用FTC標準，其中39例加用。102研究亞裔患者占25%，103研究亞裔患者占36%。替諾福韋臨床研究第8年，仍有高達64%的患者保留在研究中替諾福韋治療8年患者的保留情況1 Marcellin P, Heathcote EJ, Buti M

12、, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008;359:24422455；3 Buti M, Tsai N, Petersen J, et al. Seven-Year Efficacy and Safety of Treatment with Tenofovir Disoproxil Fumarate for Chronic Hepatitis B Virus Infection. Dig Dis Sci. DOI 10.1

13、007/s10620-014-3486-7 ; 4.Marcellin P, Gane EJ, Flisiak R, et al. Long term treatment with tenofovir disoproxil fumarate for chronic hepatitis B infection is safe and well tolerated and associated with durable virologic response with no detectable resistance: 8 year results from two phase 3 trials.H

14、epatology.2014;60(S1):313A,Abs.229；5 Heathcote EJ, Gane E, deMan R, et al. Two Year Tenofovir Disoproxil Fumarate (TDF) Treatment and Adefovir Dipivoxil (ADV) Switch Data in HBeAg-Positive Patients With Chronic Hepatitis B (Study 103). Hepatology, 2008; 48(4):suppl:376A, abstract 158；6 Marcellin P,

15、Buti M, Krastev Z, et al. Two year tenofovir disoproxil fumarate (TDF) Treatment and adefovir dipivoxil (ADV) switch Data in hbeag-negative patients with chronic Hepatitis b (study 102), preliminary analysis . Hepatology, 2008; 48(4):suppl:370A, abstract 146； 7 Heathcote EJ, Marcellin P, Buti M, et

16、al. Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B. Gastroenterology. 2011;140(1):132-43； 8 EJ Heathcote, EJ Gane, RA de Man, et al. Long term (4 year) efficacy and safety of Tenofovir disoproxil fumarate (TDF) treatment In hbeag-positive patients (

17、HBeAg+) with Chronic hepatitis b (study 103): preliminary Analysis. Hepatology, 2010; 52(4):suppl:556A, abstract 477； 9 Marcellin P, Buti M, Krastev Z, et al. Continued efficacy and safety through 4 Years of tenofovir disoproxil fumarate (TDF) Treatment in HBeAg-negative patients with Chronic hepati

18、tis B (study 102): preliminary. AnalysisHepatology, 2010; 52(4):suppl:555A, abstract 476；10 Marcellin P, Gane E, Buti M, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet. 2013;381(9865):468-75; 11

19、Tsai N, Buti M, Edward Gane E, et al. Six Years of Treatment With Tenofovir DF for Chronic Hepatitis B Virus Infection is Safe and Well Tolerated and Associated With Sustained Virological, Biochemical, and Serological Responses With No Detectable Resistance. Hepatol Int.2013; 7 (Suppl 1):11.abstract

20、:188891%64%替諾福韋治療8年，98%以上的患者達到HBV DNA400拷貝/ml (On-treatment人群) 101 Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008;359:24422455；3 Buti M, Tsai N, Petersen J, et al. Seven-Year Efficacy and Safety of Treatme

21、nt with Tenofovir Disoproxil Fumarate for Chronic Hepatitis B Virus Infection. Dig Dis Sci. DOI 10.1007/s10620-014-3486-7 ; 4.Marcellin P, Gane EJ, Flisiak R, et al. Long term treatment with tenofovir disoproxil fumarate for chronic hepatitis B infection is safe and well tolerated and associated wit

22、h durable virologic response with no detectable resistance: 8 year results from two phase 3 trials.Hepatology.2014;60(S1):313A,Abs.229；5 Heathcote EJ, Gane E, deMan R, et al. Two Year Tenofovir Disoproxil Fumarate (TDF) Treatment and Adefovir Dipivoxil (ADV) Switch Data in HBeAg-Positive Patients Wi

23、th Chronic Hepatitis B (Study 103). Hepatology, 2008; 48(4):suppl:376A, abstract 158；6 Marcellin P, Buti M, Krastev Z, et al. Two year tenofovir disoproxil fumarate (TDF) Treatment and adefovir dipivoxil (ADV) switch Data in hbeag-negative patients with chronic Hepatitis b (study 102), preliminary a

24、nalysis . Hepatology, 2008; 48(4):suppl:370A, abstract 146； 7 Heathcote EJ, Marcellin P, Buti M, et al. Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B. Gastroenterology. 2011;140(1):132-43； 8 EJ Heathcote, EJ Gane, RA de Man, et al. Long term (4 yea

25、r) efficacy and safety of Tenofovir disoproxil fumarate (TDF) treatment In hbeag-positive patients (HBeAg+) with Chronic hepatitis b (study 103): preliminary Analysis. Hepatology, 2010; 52(4):suppl:556A, abstract 477； 9 Marcellin P, Buti M, Krastev Z, et al. Continued efficacy and safety through 4 Y

26、ears of tenofovir disoproxil fumarate (TDF) Treatment in HBeAg-negative patients with Chronic hepatitis B (study 102): preliminary. AnalysisHepatology, 2010; 52(4):suppl:555A, abstract 476；10 Marcellin P, Gane E, Buti M, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumar

27、ate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet. 2013;381(9865):468-75; 11 Tsai N, Buti M, Edward Gane E, et al. Six Years of Treatment With Tenofovir DF for Chronic Hepatitis B Virus Infection is Safe and Well Tolerated and Associated With Sustained Virological, Biochemical

28、, and Serological Responses With No Detectable Resistance. Hepatol Int.2013; 7 (Suppl 1):11.abstract:1888TDF-TDF組（On-treatment分析）；TDF-TDF 和ADV-TDF兩組（On-treatment分析） 8,9 7 10 315,6 4 11替諾福韋治療慢性乙肝患者8年強效抑制病毒復制*TDF-TDF組；TDF-TDF 和ADV-TDF兩組替諾福韋治療HBeAg陽性患者8年，HBeAg消失和血清轉(zhuǎn)換率分別為47%和31%4。 替諾福韋治療慢性乙肝患者8年血清學應答 7

29、10 11 3 8*1*5 4替諾福韋治療HBeAg陽性患者8年，HBsAg消失和血清轉(zhuǎn)換率分別為13%和10%4。1 Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008;359:24422455；3 Buti M, Tsai N, Petersen J, et al. Seven-Year Efficacy and Safety of Treatment with

30、 Tenofovir Disoproxil Fumarate for Chronic Hepatitis B Virus Infection. Dig Dis Sci. DOI 10.1007/s10620-014-3486-7 ; 4.Marcellin P, Gane EJ, Flisiak R, et al. Long term treatment with tenofovir disoproxil fumarate for chronic hepatitis B infection is safe and well tolerated and associated with durab

31、le virologic response with no detectable resistance: 8 year results from two phase 3 trials.Hepatology.2014;60(S1):313A,Abs.229；5 Heathcote EJ, Gane E, deMan R, et al. Two Year Tenofovir Disoproxil Fumarate (TDF) Treatment and Adefovir Dipivoxil (ADV) Switch Data in HBeAg-Positive Patients With Chro

32、nic Hepatitis B (Study 103). Hepatology, 2008; 48(4):suppl:376A, abstract 158；6 Marcellin P, Buti M, Krastev Z, et al. Two year tenofovir disoproxil fumarate (TDF) Treatment and adefovir dipivoxil (ADV) switch Data in hbeag-negative patients with chronic Hepatitis b (study 102), preliminary analysis

33、 . Hepatology, 2008; 48(4):suppl:370A, abstract 146； 7 Heathcote EJ, Marcellin P, Buti M, et al. Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B. Gastroenterology. 2011;140(1):132-43； 8 EJ Heathcote, EJ Gane, RA de Man, et al. Long term (4 year) effi

34、cacy and safety of Tenofovir disoproxil fumarate (TDF) treatment In hbeag-positive patients (HBeAg+) with Chronic hepatitis b (study 103): preliminary Analysis. Hepatology, 2010; 52(4):suppl:556A, abstract 477； 9 Marcellin P, Buti M, Krastev Z, et al. Continued efficacy and safety through 4 Years of

35、 tenofovir disoproxil fumarate (TDF) Treatment in HBeAg-negative patients with Chronic hepatitis B (study 102): preliminary. AnalysisHepatology, 2010; 52(4):suppl:555A, abstract 476；10 Marcellin P, Gane E, Buti M, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for

36、 chronic hepatitis B: a 5-year open-label follow-up study. Lancet. 2013;381(9865):468-75; 11 Tsai N, Buti M, Edward Gane E, et al. Six Years of Treatment With Tenofovir DF for Chronic Hepatitis B Virus Infection is Safe and Well Tolerated and Associated With Sustained Virological, Biochemical, and S

37、erological Responses With No Detectable Resistance. Hepatol Int.2013; 7 (Suppl 1):11.abstract:1888替諾福韋治療高病毒載量（HVL）和非高病毒載量患者病毒學應答率相似替諾福韋治療至96周，HVL及非-HVL患者病毒學應答*率相似替諾福韋治療5年， HVL患者病毒學應答率為98.3%13*病毒學應答：HBV DNA400拷貝/ml替諾福韋治療初治HVL和非HVL患者5年，達到HBV DNA400拷貝/ml的患者比例上圖數(shù)據(jù)排除加用FTC的患者。Gordon et al, Efficacy of Ten

38、ofovir Disoproxil Fumarate at 240 Weeks in Patients With Chronic Hepatitis B With High Baseline Viral Load. Hepatology. 2013;58:505-513HVL(高病毒載量）指基線HBV DNA9log10copies/ml。入組HVL患者共129例（20%），TDF組82例， ADV組47例。Non-HVL N= 512 500 502 487 495 485 484 463 457 453 445 434 438 435 431 433 426 426 419 414 412

39、 395 396 391 387 -NonHVL N= 129 126 126 123 122 121 121 119 113 100 90 85 82 82 82 78 74 72 66 66 66 65 60 61 59在HBeAg陽性的高病毒載量初治患者中替諾福韋病毒學應答率優(yōu)于ETVHBeAg陽性高病毒載量初治患者，TDF完全病毒學應答率顯著高于ETV。Gao L, Trinh HN, Li J, Nguyen MH,et al.Tenofovir is superior to entecavir for achieving complete viral suppression in

40、HBeAg-positive chronic hepatitis B patients with high HBV DNA. Aliment Pharmacol Ther. 2014 Mar;39(6):629-37. 完全病毒抑制：HBV DNA 6log10IU/mLHBeAg陽性HBeAg陰性一項回顧性病例隊列研究，275例初治高病毒載量（ HBV DNA6 log10 IU/ml ）患者納入分析，其中59例接受TDF治療，216例接受ETV治療348例在基線和5年均接受肝活檢96例在基線時為肝硬化(Ishak評分5)252例在基線時無肝硬化(Ishak評分4)基線治療5年71例 (74

41、%)無肝硬化25例肝硬化240例 (95%)改善或未加重12例肝纖維化加重9例Ishak評分升高1分3例肝硬化*逆轉(zhuǎn)肝硬化（ regression of cirrhosis）定義為基線肝硬化患者治療后Ishak評分下降1分且組織學檢測已無肝硬化Marcellin, P, et al. Regressionofcirrhosisduringtreatmentwithtenofovir disoproxil fumarateforchronic hepatitis B: a 5-year open-label follow-up study. Lancet.2013 9; 381(9865):46

42、8-75替諾福韋治療慢乙肝患者5年有機會逆轉(zhuǎn)肝硬化，阻止肝纖維化進展Ishak 評分 2的患者: 基線為39% ，5年時上升至63% Ishak 評分 4的患者: 基線為38% ，5年時下降至12% 肝硬化患者(Ishak評分 5): 基線為28%，5年時降至8%替諾福韋治療5年纖維化分期明顯改善*進行了基線和5年肝穿的患者；其中344例進行了基線、1年、5年的肝穿*N=348Ishak 評分38%39%12%63%Patrick M, Edward G, Maria B, et al. Regressionofcirrhosisduringtreatmentwithtenofovir dis

43、oproxil fumarateforchronic hepatitis B: a 5-year open-label follow-up study. Lancet, 2013; 381(9865): 468-75.P0.001P0.001替諾福韋治療5年基線肝硬化的患者74%肝硬化逆轉(zhuǎn)有配對肝穿刺標本的患者中28% (96/348)基線肝組織學顯示肝硬化。96例基線肝硬化患者（Ishak評分56）中，74%（71/96）肝硬化逆轉(zhuǎn)；58%（56/96）的患者Ishak評分減少3分以上。Patrick M, Edward G, Maria B, et al. Regressionofcirr

44、hosisduringtreatmentwithtenofovir disoproxil fumarateforchronic hepatitis B: a 5-year open-label follow-up study. Lancet, 2013; 381(9865): 468-75.*逆轉(zhuǎn)肝硬化（ regression of cirrhosis）定義為基線肝硬化患者治療后Ishak評分下降1分且組織學檢測已無肝硬化基線肝硬化患者240周Ishak纖維化評分的變化 N=96N=24N=14N=41N=15N=1N=1替諾福韋長期治療的耐受性替諾福韋治療8年耐受性良好： 各項腎臟不良事件*

45、發(fā)生率均2.2%。從第4年開始，每年均通過DXA#掃描對骨密度（BMD）進行評估，結(jié)果顯示，平均BMD（T評分）持續(xù)保持穩(wěn)定。*腎臟不良事件：血清肌酐較基線升高0.5mg/dl或肌酐清除率50ml/min或血磷2mg/dl#DXA：雙能X線吸收法Marcellin P, Gane EJ, Flisiak R, et al. Long term treatment with tenofovir disoproxil fumarate for chronic hepatitis B infection is safe and well tolerated and associated with d

46、urable virologic response with no detectable resistance: 8 year results from two phase 3 trials.Hepatology.2014;60(S1):313A, Abs.229治療8年期間未檢測到替諾福韋相關耐藥替諾福韋治療8年，共90例患者在165個時間點符合基因型分析。65%（107/165）的患者相對于基線無變化或者不能進行基因分型。僅9.7%（16/165）的患者在pol/RT區(qū)出現(xiàn)保守位點變化。表型分析發(fā)現(xiàn)：保守性位點變化未導致TDF表型耐藥。Amoreena Corsa,Yang Liu, Jo

47、hn Flaherty, et al. No Detectable Resistance to Tenofovir Disoproxil Fumarate (TDF) in HBeAg+ and HBeAg- Patients With Chronic Hepatitis B (CHB) After Eight Years of Treatment. Presented at the 24th Conference of APASL, March 1215, 2015, Istanbul, Turkey. PP-1203基因型變化無變化無法進行基因分析多態(tài)性位點變化 保守性位點變化對慢乙肝初治

48、患者，權威指南推薦首選強效、高耐藥基因屏障藥物推薦高耐藥屏障藥物（替諾福韋或恩替卡韋）1首選恩替卡韋或替諾福韋2長期治療： 高耐藥屏障的強效NAs（恩替卡韋或替諾福韋）3首選聚乙二醇干擾素a、替諾福韋或恩替卡韋41. Guidelines for the prevention, care and treatment of persons with chronic hepatitis b infection. WHO.20152. Liaw YF, Kao JH, Piratvisuth T, et al. Asian-Pacific consensus statement on the man

49、agement of chronic hepatitis B: a 2012 update. Hepatol Int. 2012;6(3):531-5613. European Association For The Study Of The Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol. 2012;57(1):167-85 4.Anna S. F. Lok, Brian J. McMahon. Chronic Hepatitis B:

50、 Update 2009.Hepatology. 2009;50(3):1-362015 WHO2012 亞太共識2012 歐肝指南2009 美肝指南目錄慢乙肝抗病毒治療的目標與現(xiàn)狀替諾福韋在NAs初治慢乙肝患者中的療效和耐受性替諾福韋在NAs經(jīng)治慢乙肝患者中的療效和耐受性1232012年7月啟動的中國乙肝隨訪與臨床科研平臺回顧性分析了自2000年始的13,493例慢乙肝患者，發(fā)現(xiàn)高耐藥的LAM/ADV使用比例高，而低耐藥的ETV和TDF使用比例低1我國慢乙肝治療挑戰(zhàn)：高耐藥NA使用比例高，耐藥類型多樣302醫(yī)院分析了1,803例接受NAs經(jīng)治慢乙肝患者，共檢測到560例患者發(fā)生突變，其中LA

51、M耐藥類型最常見，為431/5602Jia J, Hou J, Han T, et al. CR-HepB: A new registry system for documenting and analyzing the demography, virology and medicine treatments of hepatitis B in China. Hepatology. 58(S1): 607A-26A, abstract 867.Liu Y, Wang C, Zhong Y, et al. Genotypic resistance profile of hepatitis B v

52、irus (HBV) in a large cohort of nucleos(t)ide analogue-experienced Chinese patients with chronic HBV infection J Viral Hepat. 2011;18:e29-39.NAs耐藥類型及構成比（n=560）各Nas使用比例 拉米夫定耐藥后換用ETV或LAM+ADV 療效不佳，且耐藥率高2年后的基因型耐藥率2年后的病毒學應答率（PP分析）P = 0.025 LAM耐藥后換用ETV治療2年，病毒學應答率僅為40.0% （PP分析）；累積耐藥率為24.6%。Yim HJ, Seo YS,

53、Yoon EL, et al. Adding adefovir vs. switching to entecavir for lamivudine-resistant chronic hepatitis B (ACE study): a 2-year follow-up randomized controlled trial Liver Int. 2013: 33: 24454P = 0.005 *HBV DNA44mol/l)或肌酐清除率50ml/min或PO42mg/dl (0.65mmol/l)121研究：替諾福韋治療LAM耐藥患者能獲得較高的病毒學應答率雙盲1年5年3年4年2年Fung

54、 S, Kwan P, Fabri M, et al. Randomized Comparison of Tenofovir Disoproxil Fumarate vs Emtricitabine and Tenofovir Disoproxil Fumarate in Patients with Lamivudine-resistant Chronic Hepatitis B. Gastroenterology. 2014; 146(4):980-988兩組96周均未檢測出TDF相關耐藥耐受性好，腎臟不良事件*輕微且發(fā)生率60 IU/mL患者多中心、隨機、開放性研究TDF組： 71.1%(

55、32/45)ETV+TDF組： 73,3%（33/45）和基線相比，沒有患者在多聚酶區(qū)/逆轉(zhuǎn)錄區(qū)均出現(xiàn)新發(fā)突變位點 治療48周無患者出現(xiàn)血肌酐較基線升高0.5 mg/dL;平均eGRF和平均血磷的改變也是輕微的。ETV耐藥患者 TDF單藥與TDF+ETV聯(lián)合治療療效相當P0.99CharacteristicValueAge, yr49.5 (23-65)Sex (male)39 (75.0)HBeAg positivity48 (92.3)Serum HBV DNA, log IU/mL5.41.76Serum HBsAg titer, log IU/mLa3.70.64aALT, U/L45.5 (17-951)Prior exposed NAsLAM, ADV12 (23.1)LAM, ADV, ETV39 (75.0)ETV, ADV1 (1.9)Treatment regimenTDF17 (32.7)TDF+LAM15 (28.9)TDF+ETV20 (38.5)TDF treatment duration, mon34.5 (6-55)Table 1. baseline characteristic